DESCRIPTION (Adapted from applicant's description): Carney Complex (CNC) is an autosomal dominant tumor syndrome that is best classified as a novel form of multiple endocrine neoplasia. In this application, Dr. Lawrence S. Kirschner proposes to isolate the genetic defect causing CNC and to begin the functional study of the encoded protein product. In the first portion of this study, a positional cloning strategy will be undertaken to isolate the genetic lesion responsible for CNC. 24 families with CNC have been collected, and a candidate region on chromosome 2pl6 has been defined by genetic recombination analysis. A yeast and bacterial artificial chromosome (YAC and BAG, respectively)-based contig of this area will be constructed and utilized to map expressed sequences into the minimal candidate region. Those mRNA sequences falling in the candidate interval will be cloned and screened for mutations using denaturing high performance liquid chromatography (D-HPLC) analysis. Once the CNC gene is identified, this information will be used to generate transgenic mice lacking the CNC gene, and the effects of this mutation during fetal development, especially of the endocrine system, will be examined. At the same time, mutations in the CNC gene will be sought in CNC associated sporadic tumors, such as cardiac myxomas, benign and malignant adrenal tumors, and thyroid cancers. The long-term goal of this project is to identify the role that the CNC gene product plays in the normal development of the endocrine and other systems, as well as the role that the mutated gene plays in tumorigenesis.